RESUMO
A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic ß cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining ß cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration, and cytosolic free Ca(2+). Finally, we demonstrate that T2DM patients with ß cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to ß cell physiology, and manipulation of this molecular switch may serve as a therapy in T2DM.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Tecido Adiposo/metabolismo , Animais , Complemento C3a/metabolismo , Fator D do Complemento/genética , Fator D do Complemento/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Secreção de Insulina , CamundongosRESUMO
This year, the Albert Lasker Basic Medical Research Award will be shared by Douglas Coleman and Jeffrey Friedman for their discovery of leptin, a hormone that regulates appetite and body weight. By uncovering a critical physiologic system, their discovery markedly accelerated our capacity to apply molecular and genetic techniques to understand obesity.
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Distinções e Prêmios , Leptina/genética , Leptina/metabolismo , Fisiologia/história , Apetite , História do Século XX , História do Século XXI , Humanos , Obesidade/fisiopatologia , Estados UnidosRESUMO
Biomedical research in the United States has contributed enormously to science and human health and is conducted in several thousand institutions that vary widely in their histories, missions, operations, size, and cultures. Though these institutional differences have important consequences for the research they conduct, the organizational taxonomy of US biomedical research has received scant systematic attention. Consequently, many observers and even participants are surprisingly unaware of important distinguishing attributes of these diverse institutions. This essay provides a high-level taxonomy of the institutional ecosystem of US biomedical research; illustrates key features of the ecosystem through portraits of eight institutions of varying age, size, culture, and missions, each representing a much larger class exhibiting additional diversity; and suggests topics for future research into the research output of institutional types that will be required to develop novel approaches to improving the function of the ecosystem.
Assuntos
Academias e Institutos , Pesquisa Biomédica , Organizações sem Fins Lucrativos/organização & administração , Academias e Institutos/organização & administração , Pesquisadores/organização & administração , Pesquisa Biomédica/organização & administração , Faculdades de Medicina/organização & administração , HospitaisRESUMO
The advancement of science requires the publication of research results so other scientists may examine, confirm, and build upon them, and the publishing ecosystem that mediates this process has undergone dramatic change over recent decades. This article takes a broad view of the biomedical research publishing system from its origins in the 17th century to the present day. It begins with a story from the author's lab that illustrates a scientist's complex interactions with the publishing system and then reviews the history, growth, and evolution of scientific publishing, including several recent disruptive developments: the digital transformation, the open access (OA) movement, the creation of "predatory journals," and the emergence of preprint archives. Each has influenced scientific peer review and editorial decision-making, two processes critical to the conduct of medical and scientific research and culture. After briefly discussing concerns about the impact of politics on editorial decision-making, the article closes with thoughts on the future evolution of this publishing ecosystem, which will impact the biomedical research ecosystem that depends upon it. Beyond accelerated speed and improved access to publications, the community should prioritize research aimed at further enhancing the quality and impact of published research, the core goal of the scientific enterprise.
Assuntos
Pesquisa Biomédica , Editoração , Humanos , Publicações Periódicas como Assunto , Revisão da Pesquisa por Pares , Políticas EditoriaisRESUMO
Over recent decades, progress in bioscience research has been remarkable, but alongside the many transformative advances is a growing concern that a surprisingly high fraction of published research cannot be reproduced by the scientific community. Though experimental and interpretive errors are unavoidable features of the scientific process, recent evidence suggests that irreproducibility is a serious issue requiring analysis, understanding, and remediation. This article reviews the meaning of research reproducibility, examines ongoing efforts to estimate its prevalence, and considers the factors that contribute to it. Two recent case studies illustrate the disparate responses that researchers may take when facing serious claims that a high-profile research finding is irreproducible and may be false. Finally, the article examines potential interventions to counter the current level of irreproducibility, aimed at increasing the efficiency and impact of society's substantial and critically important investment in bioscience research.
Assuntos
Reprodutibilidade dos Testes , HumanosRESUMO
Fraud in biomedical research, though relatively uncommon, damages the scientific community by diminishing the integrity of the ecosystem and sending other scientists down fruitless paths. When exposed and publicized, fraud also reduces public respect for the research enterprise, which is required for its success. Although the human frailties that contribute to fraud are as old as our species, the response of the research community to allegations of fraud has dramatically changed. This is well illustrated by three prominent cases known to the author over 40 years. In the first, I participated as auditor in an ad hoc process that, lacking institutional definition and oversight, was open to abuse, though it eventually produced an appropriate result. In the second, I was a faculty colleague of a key participant whose case helped shape guidelines for management of future cases. The third transpired during my time overseeing the well-developed if sometimes overly bureaucratized investigatory process for research misconduct at Harvard Medical School, designed in accordance with prevailing regulations. These cases illustrate many of the factors contributing to fraudulent biomedical research in the modern era and the changing institutional responses to it, which should further evolve to be more efficient and transparent.
Assuntos
Pesquisa Biomédica , Má Conduta Científica , Ecossistema , Fraude , Humanos , PesquisadoresRESUMO
The health provider workforce is shaped by factors collectively influencing the education, training, licensing, and certification of physicians and allied health professionals, through professional organizations with interlocking and often opaque governance relationships within a state-based licensing system. This system produces a workforce is that is insufficiently responsive to current needs and opportunities, including those created by new technologies. This lack of responsiveness reflects the complex, nontransparent, and cautious nature of the controlling organizations, influenced by the economic interests of the organized professions, which seek protection from competitors both local and international. The first step in addressing this is to comprehensively examine the organizational complexity and conflicted interests within this critical ecosystem. Doing so suggests areas ripe for change, to enhance the health workforce and benefit public health.
Assuntos
Credenciamento/organização & administração , Ocupações em Saúde/educação , Ocupações em Saúde/normas , Pessoal de Saúde/educação , Pessoal de Saúde/organização & administração , Mão de Obra em Saúde/organização & administração , Credenciamento/normas , Pessoal de Saúde/normas , Mão de Obra em Saúde/normas , Humanos , Melhoria de Qualidade/organização & administração , Estados UnidosRESUMO
Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to ß-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.
Assuntos
Adaptação Fisiológica/fisiologia , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Fatores de Crescimento de Fibroblastos/metabolismo , Termogênese/fisiologia , Transativadores/metabolismo , Adaptação Fisiológica/genética , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Diferenciação Celular , Células Cultivadas , Temperatura Baixa , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Processamento Pós-Transcricional do RNA , Transativadores/genética , Fatores de TranscriçãoRESUMO
Credit for scientific discovery plays a central role in the reward structure of science. As the "currency of the realm," it powerfully influences the norms and institutional practices of the research ecosystem. Though most scientists enter the field for reasons other than desiring credit, once in the field they desire credit for their work. In addition to being a source of pleasure, credit and recognition are necessary for successful careers. The consensus among sociologists, philosophers, and economists is that pursuit of credit increases the efficiency of the scientific enterprise. Publishing results in a scholarly journal is the core approach to obtaining credit and priority, and the publishing landscape is undergoing dramatic change. As research groups get larger and more interdisciplinary, and scholarly journals proliferate, allocating credit has become more difficult. Awards and prizes further contribute to credit by recognizing prior attributions and articulating new credit attributions through their decisions. Patents can have a complex relationship to credit, and disputes over authorship and credit are common and difficult to adjudicate. Pathologic pursuit of credit adversely affects the scientific enterprise. Academic institutions assess credit in appointment and promotion decisions, and are best positioned to assume responsibility for addressing problems with the credit ecosystem. Several possible remedies are presented.
Assuntos
Autoria , Mobilidade Ocupacional , Pesquisadores , Pesquisa , Academias e Institutos/organização & administração , Distinções e Prêmios , Humanos , Motivação , Patentes como Assunto , Pesquisa/organização & administração , Pesquisadores/psicologia , Publicações SeriadasRESUMO
As biomedical research has evolved over the past century, the terminology employed to categorize it has failed to evolve in parallel to accommodate the implications of these changes. In particular, the terms basic research and translational research as used today in biomedicine seem especially problematic. Here we review the origins of these terms, analyze some of the conceptual confusions attendant to their current use, and assess some of the deleterious consequences of these confusions. We summarize that the distinction between basic and translational biomedical research is an anachronism. Elimination of this often contentious distinction would improve both the culture and the effectiveness of the scientific process, and its potential benefits to society.-Flier, J. S., Loscalzo, J. Categorizing biomedical research: the basics of translation.
Assuntos
Pesquisa Translacional Biomédica/classificação , Animais , Humanos , Estudos Interdisciplinares , Projetos de Pesquisa/normas , Terminologia como Assunto , Pesquisa Translacional Biomédica/métodosRESUMO
Ingestion of very low-carbohydrate ketogenic diets (KD) is associated with weight loss, lowering of glucose and insulin levels and improved systemic insulin sensitivity. However, the beneficial effects of long-term feeding have been the subject of debate. We therefore studied the effects of lifelong consumption of this diet in mice. Complete metabolic analyses were performed after 8 and 80weeks on the diet. In addition we performed a serum metabolomic analysis and examined hepatic gene expression. Lifelong consumption of KD had no effect on morbidity or mortality (KD vs. Chow, 676 vs. 630days) despite hepatic steatosis and inflammation in KD mice. The KD fed mice lost weight initially as previously reported (Kennnedy et al., 2007) and remained lighter and had less fat mass; KD consuming mice had higher levels of energy expenditure, improved glucose homeostasis and higher circulating levels of ß-hydroxybutyrate and triglycerides than chow-fed controls. Hepatic expression of the critical metabolic regulators including fibroblast growth factor 21 were also higher in KD-fed mice while expression levels of lipogenic enzymes such as stearoyl-CoA desaturase-1 was reduced. Metabolomic analysis revealed compensatory changes in amino acid metabolism, primarily involving down-regulation of catabolic processes, demonstrating that mice eating KD can shift amino acid metabolism to conserve amino acid levels. Long-term KD feeding caused profound and persistent metabolic changes, the majority of which are seen as health promoting, and had no adverse effects on survival in mice.
RESUMO
BACKGROUND & AIMS: Nonalcoholic fatty liver disease is a common consequence of human and rodent obesity. Disruptions in lipid metabolism lead to accumulation of triglycerides and fatty acids, which can promote inflammation and fibrosis and lead to nonalcoholic steatohepatitis. Circulating levels of fibroblast growth factor (FGF)21 increase in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis; therefore, we assessed the role of FGF21 in the progression of murine fatty liver disease, independent of obesity, caused by methionine and choline deficiency. METHODS: C57BL/6 wild-type and FGF21-knockout (FGF21-KO) mice were placed on methionine- and choline-deficient (MCD), high-fat, or control diets for 8-16 weeks. Mice were weighed, and serum and liver tissues were collected and analyzed for histology, levels of malondialdehyde and liver enzymes, gene expression, and lipid content. RESULTS: The MCD diet increased hepatic levels of FGF21 messenger RNA more than 50-fold and serum levels 16-fold, compared with the control diet. FGF21-KO mice had more severe steatosis, fibrosis, inflammation, and peroxidative damage than wild-type C57BL/6 mice. FGF21-KO mice had reduced hepatic fatty acid activation and ß-oxidation, resulting in increased levels of free fatty acid. FGF21-KO mice given continuous subcutaneous infusions of FGF21 for 4 weeks while on an MCD diet had reduced steatosis and peroxidative damage, compared with mice not receiving FGF21. The expression of genes that regulate inflammation and fibrosis were reduced in FGF21-KO mice given FGF21, similar to those of wild-type mice. CONCLUSIONS: FGF21 regulates fatty acid activation and oxidation in livers of mice. In the absence of FGF21, accumulation of inactivated fatty acids results in lipotoxic damage and increased steatosis.
Assuntos
Deficiência de Colina/complicações , Ácidos Graxos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Metionina/deficiência , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Modelos Animais de Doenças , Progressão da Doença , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/deficiência , Fatores de Crescimento de Fibroblastos/genética , Hepatite/genética , Hepatite/metabolismo , Hepatite/prevenção & controle , Mediadores da Inflamação/metabolismo , Infusões Subcutâneas , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução , RNA Mensageiro/metabolismo , Proteínas Recombinantes/administração & dosagem , Índice de Gravidade de Doença , Fatores de TempoRESUMO
This commentary documents how federal funding agencies are changing the criteria by which they distribute taxpayer money intended for scientific research. Increasingly, STEMM (Science, Technology, Engineering, Mathematics, and Medicine) funding agencies are requiring applicants for funding to include a plan to advance DEI ("Diversity, Equity, and Inclusion") in their proposals and to dedicate a part of the research budget to its implementation. These mandates undermine the academic freedom of researchers and the unbiased generation of knowledge needed for a well-functioning democracy. Maintaining excellence in science is fundamental to the continuation of the U.S. as a global economic leader. Science provides a basis for solving important global challenges such as security, energy, climate, and health. Diverting funding from science into activities unrelated to the production of knowledge undermines science's ability to serve humankind. When funding agencies politicize science by using their power to further a particular ideological agenda, they contribute to public mistrust in science. Hijacking science funding to promote DEI is thus a threat to our society.
RESUMO
New applications of evolutionary biology in medicine are being discovered at an accelerating rate, but few physicians have sufficient educational background to use them fully. This article summarizes suggestions from several groups that have considered how evolutionary biology can be useful in medicine, what physicians should learn about it, and when and how they should learn it. Our general conclusion is that evolutionary biology is a crucial basic science for medicine. In addition to looking at established evolutionary methods and topics, such as population genetics and pathogen evolution, we highlight questions about why natural selection leaves bodies vulnerable to disease. Knowledge about evolution provides physicians with an integrative framework that links otherwise disparate bits of knowledge. It replaces the prevalent view of bodies as machines with a biological view of bodies shaped by evolutionary processes. Like other basic sciences, evolutionary biology needs to be taught both before and during medical school. Most introductory biology courses are insufficient to establish competency in evolutionary biology. Premedical students need evolution courses, possibly ones that emphasize medically relevant aspects. In medical school, evolutionary biology should be taught as one of the basic medical sciences. This will require a course that reviews basic principles and specific medical applications, followed by an integrated presentation of evolutionary aspects that apply to each disease and organ system. Evolutionary biology is not just another topic vying for inclusion in the curriculum; it is an essential foundation for a biological understanding of health and disease.
Assuntos
Evolução Biológica , Biologia/educação , Educação Médica , Currículo , HumanosRESUMO
The increased prevalence of obesity in recent decades is a topic of great scientific and medical interest, but despite many advances, the causes of this increase have not been adequately identified. In this context, two conflicting models for obesity-the carbohydrate-insulin model (CIM) and the energy balance model (EBM)-are being vigorously debated by distinct cohorts of experts in the field. The goal of this perspective is to assess this "conflict of models" from a neutral perspective. I conclude that although both models have produced useful insights, they differ fundamentally in what they seek to explain, and neither has yet provided a validated mechanistic account for the rising obesity prevalence in some but not all members of the population. Rather than engaging in such debates over competing models, the field should be more focused on establishing specific mechanistic insights in identified patient groups and, eventually, actionable interventions based on them.
Assuntos
Insulina , Obesidade , Humanos , Obesidade/epidemiologia , CarboidratosRESUMO
In an effort to identify novel candidate regulators of adipogenesis, gene profiling of differentiating 3T3-L1 preadipocytes was analyzed using a novel algorithm. We report here the characterization of xanthine oxidoreductase (XOR) as a novel regulator of adipogenesis. XOR lies downstream of C/EBPbeta and upstream of PPARgamma, in the cascade of factors that control adipogenesis, and it regulates PPARgamma activity. In vitro, knockdown of XOR inhibits adipogenesis and PPARgamma activity while constitutive overexpression increases activity of the PPARgamma receptor in both adipocytes and preadipocytes. In vivo, XOR -/- mice demonstrate 50% reduction in adipose mass versus wild-type littermates while obese ob/ob mice exhibit increased concentrations of XOR mRNA and urate in the adipose tissue. We propose that XOR is a novel regulator of adipogenesis and of PPARgamma activity and essential for the regulation of fat accretion. Our results identify XOR as a potential therapeutic target for metabolic abnormalities beyond hyperuricemia.
Assuntos
Adipogenia , PPAR gama/genética , PPAR gama/metabolismo , Xantina Desidrogenase/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/enzimologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/enzimologia , Adiposidade/efeitos dos fármacos , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Tamanho do Órgão/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Rosiglitazona , Tiazolidinedionas/farmacologia , Xantina Desidrogenase/deficiência , Xantina Desidrogenase/genéticaRESUMO
This an edited transcript of the Lee E. Farr Lecture given by Dr. Jeffrey Flier on May 8, 2012, at the culmination of the annual Student Research Day at the Yale School of Medicine. In this presentation, Dr. Flier discusses his and his wife's research on insulin, leptin, and FGF21 in the context of his reflections upon his life's work and his advice for young investigators.
Assuntos
Diabetes Mellitus/fisiopatologia , Fatores de Crescimento de Fibroblastos/metabolismo , Resistência à Insulina , Insulina/metabolismo , Leptina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Peso Corporal , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Dieta Cetogênica , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Fatores de Crescimento de Fibroblastos/genética , Humanos , Insulina/genética , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/fisiopatologiaRESUMO
The neuropeptide AgRP promotes food intake and weight gain by antagonizing signaling at melanocortin 3 and 4 receptors in the brain, but the limited phenotype of mice lacking AgRP raised questions about its importance. Four recent studies addressed this by creating mice in which AgRP neurons, which also express NPY and GABA, are ablated postnatally, and although details vary, they suggest that AgRP neurons are more essential to feeding and weight gain than is AgRP itself. A recent paper in Cell Metabolism (Wortley et al., 2005) indicates that AgRP itself is important for feeding and weight gain, but only as mice age, and the mechanism may involve dysfunction of the thyroid axis.
Assuntos
Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Neurônios/metabolismo , Proteínas/metabolismo , Aumento de Peso/fisiologia , Fatores Etários , Proteína Relacionada com Agouti , Animais , Ingestão de Alimentos/genética , Regulação da Expressão Gênica/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Knockout , Aumento de Peso/genéticaRESUMO
Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism.